Pancreatic adenocarcinomas (PDAC) are the 4th leading cause of cancer deaths in the western world and have the worst prognosis of any cancer with a five-year survival of less than 5%. PDAC develops from pre-neoplasia through various stages of non-invasive neoplastic lesions called PanIN to invasive carcinoma. Current treatments of invasive PDAC including the addition of new biologically targeted therapies to chemotherapy have little impact on overall survival. This R21 proposal focuses at better understanding how initiating oncogenic mutations found in PanIN lesions alter cell signaling pathways, how these pathways influence the phenotype of the cell and whether targeting these pathways will prevent the progression of early lesions to invasive carcinoma. In this context, we found using novel PanIN models from transgenic mice and from human pancreas cells that aberrant activities of erbB kinases and STAT3 occur in early stage PanlN lesions. We will test the hypothesis that hyperactivity of erbB kinases causing aberrant and constitutive activation of STAT3 are early events in pancreatic carcinogenesis and that synergy between these molecular events leads to the establishment of intraductal neoplastic lesions (PanIN) and are required for the progression of these lesions to invasive carcinoma. Two specific aims are proposed. (1) To establish the functional relationship between erbB kinases and STAT3 activation in mediating the tumorigenic properties of PanIN. In this aim the roles of erbB kinase signaling and STAT3 transcriptional activities in mediating the tumorigenic properties of PanIN will be determined, (2) Determine in vivo, whether functional blockade of signaling by erbB kinases and/or STAT3 activity prevents the establishment and/or progression of PanIN to invasive carcinoma. This aim will use in vivo models to determine whether inhibiting erbB kinases and STAT3 activities prevent the establishment and progression of PanIN lesions. In addition, studies will assess whether inhibiting erbB kinases and/or STAT3 are sufficient in vivo for preventing the activation of down stream molecular targets and whether the activation status of these targets are predictors of response to therapy. Overall, these studies will use innovative models to provide a better understanding of the mechanisms involved in the establishment and progression of PDAC and determine whether this information can be translated to prevention or therapy using clinically relevant drugs. [unreadable] [unreadable] [unreadable]